Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.

BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

PSMA PET/CT: joint EANM procedure guideline/SNMMI procedure standard for prostate cancer imaging 2.0.

Here we aim to provide updated guidance and standards for the indication, acquisition, and interpretation of PSMA PET/CT for prostate cancer imaging. Procedures and characteristics are reported for a variety of available PSMA small radioligands. Different scenarios for the clinical use of PSMA-ligand PET/CT are discussed. This document provides clinicians and technicians with the best available evidence, to support the implementation of PSMA PET/CT imaging in research and routine practice.

Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

18F-DCFPyL PET/CT for Initially Diagnosed and Biochemically Recurrent Prostate Cancer: Prospective Trial with Pathologic Confirmation.

Background Prostate-specific membrane antigen (PSMA) PET is standard for newly diagnosed high-risk and biochemically recurrent (BCR) prostate cancer. Although studies suggest high specificity of 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL) for targeting PSMA, false-positive findings have been identified and most studies lack histologic confirmation of malignancy. Purpose To estimate the positive predictive value (PPV) of DCFPyL PET/CT by providing histopathologic proof for DCFPyL-avid lesions suspected of being distant metastases at initial diagnosis and recurrence in BCR prostate cancer. Materials and Methods In this prospective trial, men with newly diagnosed high-risk prostate cancer (sample 1) or BCR prostate cancer and negative findings at conventional CT and/or bone scanning (sample 2) were enrolled between January and December 2021. All men underwent DCFPyL PET/CT. Suspected distant metastases and/or recurrences were biopsied. PPV was calculated. Results A total of 92 men with newly diagnosed prostate cancer (median age, 70 years; IQR, 64-75 years) (sample 1) and 92 men with BCR prostate cancer (median age, 71 years; IQR, 66-75 years) (sample 2) were enrolled. In sample 1, 25 of the 92 men (27%) demonstrated DCFPyL-avid lesions suspicious for distant metastases. Biopsy was performed in 23 of the 25 men (92%), with 17 of the 23 (74%) biopsies positive for malignancy and six (26%) benign. Of the six benign biopsies, three were solitary rib foci and three were solitary pelvic bone foci. In sample 2, 57 of the 92 men (62%) demonstrated DCFPyL-avid lesions suspicious for recurrence. Biopsy was performed in 37 of the 57 men (65%), with 33 of the 37 (89%) biopsies positive for malignancy and four (11%) benign. Of the four benign biopsies, two were subcentimeter pelvic nodes and/or nodules, one was a rib, and one was a pelvic bone focus. Conclusion PET/CT with 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL) had a high biopsy-proven positive predictive value for distant metastases in newly diagnosed prostate cancer (74%) and for recurrence sites in men with biochemical recurrence (89%). However, there were DCFPyL-avid false-positive findings (particularly in ribs and pelvic bones). Solitary DCFPyL avidity in these locations should not be presumed as malignant. Biopsy may still be needed prior to therapy decisions. ClinicalTrials.gov registration no. NCT04700332 © RSNA, 2022 See also the editorial by Zukotynski and Kuo in this issue.

Diagnostic performance of 18 F-FDG-PET/CT compared to standard skeletal survey for detecting bone destruction in smouldering multiple myeloma: time to move forward.

Skeletal survey (SS) continues to be used in the community to detect bone disease in patients with multiple myeloma (MM). While the false-negative rate is high, the specificity of SS is less well characterised. Here, we compare the diagnostic accuracy of SS compared to 18 F-FDG-PET/CT (positron emission tomography/computed tomography) in 79 patients referred to our tertiary centre with a diagnosis of smouldering MM. SS had a specificity of 83·1% (95% confidence interval: 72·0-90·5%). This study reinforces the importance of using more specific imaging techniques to avoid inaccurate diagnosis that could lead to the risks associated with unnecessary therapy in patients with smouldering MM.

Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma.

LESSONS LEARNED: Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing. Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T-cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response. BACKGROUND: Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof-of-principle pilot study to evaluate the synergy between the combination of the anti-PD-L1, avelumab, and concomitant hypofractionated radiotherapy. METHODS: This was a single-arm phase II Simon two-stage single center study that was prematurely terminated because of the COVID-19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect. RESULTS: At a median potential follow-up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5-7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1-2 treatment-related adverse events. CONCLUSION: Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

BACKGROUND: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma. METHODS: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999. FINDINGS: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths. INTERPRETATION: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies. FUNDING: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.

Evaluating Biochemically Recurrent Prostate Cancer: Histologic Validation of 18F-DCFPyL PET/CT with Comparison to Multiparametric MRI.

Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) may improve detection of recurrence compared with multiparametric MRI; however, histopathologic validation is lacking. Purpose To determine the sensitivity, specificity, and positive predictive value (PPV) of 18F-DCFPyL PET/CT based on histologic analysis and to compare with pelvic multiparametric MRI in men with biochemically recurrent prostate cancer. Materials and Methods Men were prospectively recruited after prostatectomy and/or radiation therapy with rising prostate-specific antigen level (median, 2.27 ng/mL; range, 0.2-27.45 ng/mL) and a negative result at conventional imaging (bone scan and/or CT). Participants underwent 18F-DCFPyL PET/CT imaging and 3.0-T pelvic multiparametric MRI. Statistical analysis included Wald and modified χ2 tests. Results A total of 323 lesions were visualized in 77 men by using 18F-DCFPyL or multiparametric MRI, with imaging detection concordance of 25% (82 of 323) when including all lesions in the MRI field of view and 53% (52 of 99) when only assessing prostate bed lesions. 18F-DCFPyL depicted more pelvic lymph nodes than did MRI (128 vs 23 nodes). Histologic validation was obtained in 80 locations with sensitivity, specificity, and PPV of 69% (25 of 36; 95% confidence interval [CI]: 51%, 88%), 91% (40 of 44; 95% CI: 74%, 98%), and 86% (25 of 29; 95% CI: 73%, 97%) for 18F-DCFPyL and 69% (24 of 35; 95% CI: 50%, 86%), 74% (31 of 42; 95% CI: 42%, 89%), and 69% (24 of 35; 95% CI: 50%, 88%) for multiparametric MRI (P = .95, P = .14, and P = .07, respectively). In the prostate bed, sensitivity, specificity, and PPV were 57% (13 of 23; 95% CI: 32%, 81%), 86% (18 of 21; 95% CI: 73%, 100%), and 81% (13 of 16; 95% CI: 59%, 100%) for 18F-DCFPyL and 83% (19 of 23; 95% CI: 59%, 100%), 52% (11 of 21; 95% CI: 29%, 74%), and 66% (19 of 29; 95% CI: 44%, 86%) for multiparametric MRI (P = .19, P = .02, and P = .17, respectively). The addition of 18F-DCFPyL to multiparametric MRI improved PPV by 38% overall (P = .02) and by 30% (P = .09) in the prostate bed. Conclusion Findings with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) were histologically validated and demonstrated high specificity and positive predictive value. In the pelvis, 18F-DCFPyL depicted more lymph nodes and improved positive predictive value and specificity when added to multiparametric MRI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zukotynski and Rowe in this issue.

Ferumoxytol-Enhanced MR Lymphography for Detection of Metastatic Lymph Nodes in Genitourinary Malignancies: A Prospective Study.

OBJECTIVE. The objective of our study was to evaluate the utility of ferumoxytol-enhanced MR lymphography (MRL) in detection of metastatic lymph nodes (LNs) in patients with prostate, bladder, and kidney cancer. SUBJECTS AND METHODS. This phase 2 single-institution study enrolled patients with confirmed prostate (arm 1), bladder (arm 2), and kidney (arm 3) cancer and evidence of suspected LN involvement. Participants underwent ferumoxytol-enhanced MRL 24 and 48 hours after IV injection of 7.5 mg Fe/kg of ferumoxytol. A retrospective quantitative analysis was performed to determine the optimal timing for ferumoxytol-enhanced MRL using percentage change in normalized signal intensity (SI) from baseline to 24 and 48 hours after injection, which were estimated using the linear mixed-effects model in which time (24 vs 48 hours), diseases status, and time and disease status interaction were the fixed-effects independent variables. Differences in normalized SI values between subgroups of lesions were estimated by forming fixed-effects contrasts and tested by the Wald test. RESULTS. Thirty-nine patients (n = 30, arm 1; n = 6, arm 2; n = 3, arm 3) (median age, 65 years) with 145 LNs (metastatic, n = 100; benign, n = 45) were included. LN-based sensitivity, specificity, positive predictive value, and negative predictive value of ferumoxytol-enhanced MRL was 98.0%, 64.4%, 86.0%, and 93.5%, respectively. Sensitivity and specificity of ferumoxytol-enhanced MRL did not vary by LN size. Metastatic LNs showed a significantly higher percentage decrease of normalized SI on MRL at 24 hours after ferumoxytol injection than at 48 hours after ferumoxytol injection (p = 0.023), whereas the normalized SI values for nonmetastatic LNs were similar at both imaging time points (p = 0.260). CONCLUSION. Ferumoxytol-enhanced MRL shows high sensitivity in the detection of metastatic LNs in genitourinary cancers independent of LN size. The SI difference between benign and malignant LNs on ferumoxytol-enhanced MRL appears similar 24 and 48 hours after ferumoxytol injection, suggesting that imaging can be performed safely within 1 or 2 days of injection. Although ferumoxytol-enhanced MRL can be useful in settings without an available targeted PET agent, issues of iron overload and repeatability of ferumoxytol-enhanced MRL remain concerns for this method.

PET imaging in renal cancer.

PURPOSE OF REVIEW: Worldwide, over 400 000 new cases of kidney cancer were diagnosed and over 175 000 deaths anticipated in 2018. It is ranked as the 14th most common cancer in women and 9th most common in men. Imaging is important for initial detection, staging, and monitoring to assist treatment planning, but conventional anatomic imaging is limited. Although functional PET/CT has proven helpful in the diagnosis and management of many cancers, its value in renal cell carcinoma (RCC) is still in evolution. RECENT FINDINGS: FDG is probably the most useful radiotracer in RCC, although CAIX imaging can be helpful in clear cell RCC. Current research on PET imaging agents in RCC including 89Zr bevacizumab, 89Zr geruntuximab, 18F fluoro-L-thymidine (FLT), prostate-specific membrane antigen (PSMA), 11C choline, 18F sodium fluoride (NaF), and18F fluorodeoxyglucose (FDG) have shown some interesting results for detection and prognosis of the disease. SUMMARY: Many innovative radiotracers have been tested in RCC, but robust differentiation of primary disease from normal parenchyma remains elusive for almost all of them. The metastatic setting and response to therapy for this cancer are more favorable PET applications. Continued research in promising molecular tracers will hopefully advance both diagnostic and therapeutic strategies to ultimately eradicate RCC.

Novel Imaging in Detection of Metastatic Prostate Cancer.

PURPOSE OF REVIEW: This review aims to highlight the limitations of current standard-of-care prostate cancer (PCa) imaging and discuss novel clinical imaging in advanced disease. RECENT FINDINGS: PCa staging through imaging is important for proper selections in clinical treatment. Traditional imaging techniques for metastatic disease (i.e., computed tomography [CT], magnetic resonance imaging [MRI], and radionuclide bone scan) have suboptimal performance in early recurrent or metastatic disease. Novel positron emission tomography agents including radiolabeled prostate specific membrane antigen (PSMA), choline, and anti-18F-fluorocyclobutane-1-carboxylic acid (18F-FACBC) have demonstrated improved sensitivity and specificity in initial staging and early biochemical recurrence (BCR). Conventional imaging modalities for PCa incompletely characterize disease burden. The development of new PET tracers in combination with CT and MRI offers superior anatomic localization and biologic correlation of tumor sites, which enhance providers' abilities to make appropriate decisions regarding treatment.

PET imaging of recurrent and metastatic prostate cancer with novel tracers.

Early detection of recurrent prostate cancer (PCa) is of paramount importance to deliver prompt and accurate therapy reducing the chance of progression to metastatic disease. However, current imaging modalities such as conventional computed tomography, MRI and PET scanning do not provide sufficient sensitivity, especially at lower prostate-specific antigen values. Moreover, biological characterization of PCa has become increasingly important to provide patient-specific therapy and current imaging poorly characterizes disease aggressiveness. The current uprise of novel PET tracers in recurrent and metastatic PCa shows promising, yet variable sensitivities and specificities in detection, indicating the need for further studies. In this review, we highlight current and new PET tracers that have been developed to improve the detection of recurrent and metastatic PCa.

Prostate Cancer Imaging with Novel PET Tracers.

Molecular imaging of prostate cancer is in a dynamic phase of development. Currently approved techniques are limited and researchers have been working on novel agents to improve accuracy in targeting and detecting prostate tumors. In addition, the complexity of various prostate cancer states also contributes to the challenges in evaluating suitable radiotracer candidates. We have highlighted nuclear medicine tracers that focus on mechanisms involved in bone metastasis, prostate cancer cell membrane synthesis, amino acid analogs, androgen analogs, and the prostate specific membrane antigen. Encouraging results with many of these innovative radiotracer compounds will not only advance diagnostic capabilities for prostate cancer but open opportunities for theranostic applications to treat this worldwide malignancy.

[¹8F]fluciclatide in the in vivo evaluation of human melanoma and renal tumors expressing αvß 3 and α vß 5 integrins.

PURPOSE: [(18)F]Fluciclatide is an integrin-targeted PET radiopharmaceutical. αvß3 and αvß5 are upregulated in tumor angiogenesis as well as on some tumor cell surfaces. Our aim was to use [(18)F]fluciclatide (formerly known as [(18)F]AH111585) for PET imaging of angiogenesis in melanoma and renal tumors and compare with tumor integrin expression. METHODS: Eighteen evaluable patients with solid tumors ≥2.0 cm underwent [(18)F]fluciclatide PET/CT. All patients underwent surgery and tumor tissue samples were obtained. Immunohistochemical (IHC) staining with mouse monoclonal antibodies and diaminobenzidine (DAB) was applied to snap-frozen tumor specimens, and additional IHC was done on formalin-fixed paraffin-embedded samples. DAB optical density (OD) data from digitized whole-tissue sections were compared with PET SUV80% max, and Patlak influx rate constant (K i) data, tumor by tumor. RESULTS: Tumors from all 18 patients demonstrated measurable [(18)F]fluciclatide uptake. At the final dynamic time-point (55 min after injection), renal malignancies (in 11 patients) demonstrated an average SUV80% max of 6.4 ± 2.0 (range 3.8 - 10.0), while the average SUV80% max for metastatic melanoma lesions (in 6 patients) was 3.0 ± 2.0 (range 0.7 - 6.5). There was a statistically significant difference in [(18)F]fluciclatide uptake between chromophobe and nonchromophobe renal cell carcinoma (RCCs, with SUV80% max of 8.2 ± 1.8 and 5.4 ± 1.4 (P = 0.020) and tumor-to-normal kidney (T/N) ratios of 1.5 ± 0.4 and 0.9 ± 0.2, respectively (P = 0.029). The highest Pearson's correlation coefficients were obtained when comparing Patlak K i and αvß5 OD when segregating the patient population between melanoma and RCC (r = 0.83 for K i vs. melanoma and r = 0.91 for K i vs. RCC). SUV80% max showed a moderate correlation with αvß5 and αvß3 OD. CONCLUSION: [(18)F]Fluciclatide PET imaging was well tolerated and demonstrated favorable characteristics for imaging αvß3 and αvß5 expression in melanoma and RCC. Higher uptake was observed in chromophobe than in nonchromophobe RCC. [(18)F]Fluciclatide may be a useful radiotracer to improve knowledge of integrin expression.

Advances in PET Imaging of the CXCR4 Receptor: [68Ga]Ga-PentixaFor.

[68Ga]Ga-PentixaFor, a PET agent targeting CXCR4 is emerging as a versatile radiotracer with promising applications in oncology, cardiology and inflammatory disease. Preclinical work in various cancer cell lines have demonstrated high specificity and selectivity. In human investigations of several tumors, the most promising applications may be in multiple myeloma, certain lymphomas and myeloproliferative neoplasms. In the nononcologic setting, [68Ga]Ga-PentixaFor could greatly improve detection for primary aldosteronism and other endocrine abnormalities. Similarly, atherosclerotic disease and other inflammatory conditions could also benefit from enhanced identification by CXCR4 targeting. Rapidly cleared from the body with a favorable imaging and radiation dosimetry profile that has been already studied in over 1000 patients, [68Ga]Ga-PentixaFor is a worthy agent for further clinical exploration with potential for theranostic applications in hematologic malignancies.

Salivary excretion of systemically injected [18F]DCFPyL in prostate cancer patients undergoing PSMA scans.

Introduction: Prostate-specific membrane antigen (PSMA) is present in high amounts in salivary glands, but it is unclear whether labeled binders of PSMA are excreted in the saliva. Methods: Ten patients with prostate cancer underwent whole-body [18F]DCFPyL PET/CT (NCT03181867), and saliva samples were collected between 0-120 minutes post-injection. [18F]DCFPyL salivary excretion was measured over 120 minutes and expressed as %ID/g. Protein-associated binding was estimated by the percentage of [18F]DCFPyL versus parent radiotracer. Results: All PET scans of 10 patients (69 ± 8 years) with histologically confirmed prostate cancer (PSA= 2.4 ± 2.4, and Gleason Grade = 6-9) showed high uptake of [18F]-DCFPyL in salivary glands while 8 patients demonstrated high uptake in the saliva at 45 minutes. The intact [18F]-DCFPyL (98%) was also confirmed in the saliva samples at 120 min with increasing salivary radioactivity between 30-120 min. Conclusion: Systemically injected [18F]DCFPyL shows salivary gland uptake, an increasing amount of which is secreted in saliva over time and is not maximized by 120 minutes post-injection. Although probably insignificant for diagnostic studies, patients undergoing PSMA-targeted therapies should be aware of radioactivity in saliva.

Predicting 18F-DCFPyL-PET/CT Scan Positivity in Prostate Cancer Patients with Biochemical Recurrence.

RATIONALE AND OBJECTIVES: To analyze variables that can predict the positivity of 18F-DCFPyL- positron emission tomography/computed tomography (PET/CT) and extent of disease in patients with biochemically recurrent (BCR) prostate cancer after primary local therapy with either radical prostatectomy or radiation therapy. MATERIALS AND METHODS: This is a retrospective analysis of a prospective single institutional review board-approved study. We included 199 patients with biochemical recurrence and negative conventional imaging after primary local therapies (radical prostatectomy n = 127, radiation therapy n = 72). All patients underwent 18F-DCFPyL-PET/CT. Univariate and multivariate logistic regression analyses were used to determine predictors of a positive scan for both cohort of patients. Regression-based coefficients were used to develop nomograms predicting scan positivity and extra-pelvic disease. Decision curve analysis (DCA) was implemented to quantify nomogram's clinical benefit. RESULTS: Of the 127 (63%) post-radical prostatectomy patients, 91 patients had positive scans - 61 of those with intrapelvic lesions and 30 with extra-pelvic lesions (i.e., retroperitoneal or distant nodes and/or bone/organ lesions). Of the 72 post-radiation therapy patients, 65 patients had positive scans - 39 of them had intrapelvic lesions and 26 extra-pelvic lesions. In the radical prostatectomy cohort, multivariate regression analysis revealed original International Society of Urological Pathology category, prostate-specific antigen (PSA), prostate-specific antigen doubling time (PSAdt), and time from BCR (mo) to scan were predictors for scan positivity and presence of extra-pelvic disease, with an area under the curve of 80% and 78%, respectively. Positive versus negative tumor margin after radical prostatectomy was not related to scan positivity or to the presence of positive extra-pelvic foci. In the radiation therapy cohort, multivariate regression analysis revealed that PSA, PSAdt, and time to BCR (mo) were predictors of extra-pelvic disease, with area under the curve of 82%. Because only seven patients in the radiation therapy cohort had negative scans, a prediction model for scan positivity could not be analyzed and only the presence of extra-pelvic disease was evaluated. CONCLUSION: PSA and PSAdt are consistently significant predictors of 18F-DCFPyL PET/CT positivity and extra-pelvic disease in BCR prostate cancer patients. Stratifying the patient population into primary local treatment group enables the use of other variables as predictors, such as time since BCR. This nomogram may guide selection of the most suitable candidates for 18F-DCFPyL-PET/CT imaging.

Reducing False-Positives Due to Urinary Stagnation in the Prostatic Urethra on 18 F-DCFPyL PSMA PET/CT With MRI.

PURPOSE: Prostate-specific membrane antigen (PSMA)-targeting PET radiotracers reveal physiologic uptake in the urinary system, potentially misrepresenting activity in the prostatic urethra as an intraprostatic lesion. This study examined the correlation between midline 18 F-DCFPyL activity in the prostate and hyperintensity on T2-weighted (T2W) MRI as an indication of retained urine in the prostatic urethra. PATIENTS AND METHODS: Eighty-five patients who underwent both 18 F-DCFPyL PSMA PET/CT and prostate MRI between July 2017 and September 2023 were retrospectively analyzed for midline radiotracer activity and retained urine on postvoid T2W MRIs. Fisher's exact tests and unpaired t tests were used to compare residual urine presence and prostatic urethra measurements between patients with and without midline radiotracer activity. The influence of anatomical factors including prostate volume and urethral curvature on urinary stagnation was also explored. RESULTS: Midline activity on PSMA PET imaging was seen in 14 patients included in the case group, whereas the remaining 71 with no midline activity constituted the control group. A total of 71.4% (10/14) and 29.6% (21/71) of patients in the case and control groups had urethral hyperintensity on T2W MRI, respectively ( P < 0.01). Patients in the case group had significantly larger mean urethral dimensions, larger prostate volumes, and higher incidence of severe urethral curvature compared with the controls. CONCLUSIONS: Stagnated urine within the prostatic urethra is a potential confounding factor on PSMA PET scans. Integrating PET imaging with T2W MRI can mitigate false-positive calls, especially as PSMA PET/CT continues to gain traction in diagnosing localized prostate cancer.

Deep learning-based whole-body PSMA PET/CT attenuation correction utilizing Pix-2-Pix GAN.

PURPOSE: Sequential PET/CT studies oncology patients can undergo during their treatment follow-up course is limited by radiation dosage. We propose an artificial intelligence (AI) tool to produce attenuation-corrected PET (AC-PET) images from non-attenuation-corrected PET (NAC-PET) images to reduce need for low-dose CT scans. METHODS: A deep learning algorithm based on 2D Pix-2-Pix generative adversarial network (GAN) architecture was developed from paired AC-PET and NAC-PET images. 18F-DCFPyL PSMA PET-CT studies from 302 prostate cancer patients, split into training, validation, and testing cohorts (n = 183, 60, 59, respectively). Models were trained with two normalization strategies: Standard Uptake Value (SUV)-based and SUV-Nyul-based. Scan-level performance was evaluated by normalized mean square error (NMSE), mean absolute error (MAE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR). Lesion-level analysis was performed in regions-of-interest prospectively from nuclear medicine physicians. SUV metrics were evaluated using intraclass correlation coefficient (ICC), repeatability coefficient (RC), and linear mixed-effects modeling. RESULTS: Median NMSE, MAE, SSIM, and PSNR were 13.26%, 3.59%, 0.891, and 26.82, respectively, in the independent test cohort. ICC for SUVmax and SUVmean were 0.88 and 0.89, which indicated a high correlation between original and AI-generated quantitative imaging markers. Lesion location, density (Hounsfield units), and lesion uptake were all shown to impact relative error in generated SUV metrics (all p < 0.05). CONCLUSION: The Pix-2-Pix GAN model for generating AC-PET demonstrates SUV metrics that highly correlate with original images. AI-generated PET images show clinical potential for reducing the need for CT scans for attenuation correction while preserving quantitative markers and image quality.

A Phase 1 Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy.

PURPOSE: NCT03253744 is a phase 1 trial with the primary objective to identify the maximum tolerated dose (MTD) of salvage stereotactic body radiation therapy (SBRT) in patients with local prostate cancer recurrence after brachytherapy. Additional objectives included biochemical control and imaging response. METHODS AND MATERIALS: This trial was initially designed to test 3 therapeutic dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions. Intensity modulation was used to deliver the prescription dose to the magnetic resonance imaging and prostate-specific membrane antigen-based positron emission tomography imaging-defined gross tumor volume while simultaneously delivering 30 Gy to an elective volume defined by the prostate gland. This phase 1 trial followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until trial completion at 2 years post-SBRT using Common Terminology Criteria for Adverse Events version 5.0. Escalation was halted if 2 dose limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT or any grade ≥3 genitourinary (GU) or grade 4 gastrointestinal toxicity thereafter. RESULTS: Between August 2018 and January 2023, 9 patients underwent salvage SBRT and were observed for a median of 22 months (Q1-Q3, 20-43 months). No grade 3 to 5 adverse events related to study treatment were observed; thus, no dose limiting toxicities occurred during the observation period. Escalation was halted by amendment given excellent biochemical control in DL1 and DL2 in the setting of a high incidence of clinically significant late grade 2 GU toxicity. Therefore, the MTD was considered 42.5 Gy in 5 fractions (DL2). One- and 2-year biochemical progression-free survival were 100% and 86%, representing a single patient in the trial cohort with biochemical failure (prostate-specific antigen [PSA] nadir + 2.0) at 20 months posttreatment. CONCLUSIONS: The MTD of salvage SBRT for the treatment of intraprostatic radiorecurrence after brachytherapy was 42.5 Gy in 5 fractions producing an 86% 2-year biochemical progression-free survival rate, with 1 poststudy failure at 20 months. The most frequent clinically significant toxicity was late grade 2 GU toxicity.